Our central hypothesis in the Michigan MAPP Discovery Site is that a subset of women with IC/PBS has a "central" problem in pain or sensory processing, as occurs in fibromyalgia (FM), rather than a disorder confined to the bladder. Project 3 will further explore the precise reason(s) for the augmented pain and sensory processing seen in IC/PBS. In this study, a specific molecular probe will be administered to IC/PBS patients to test whether a subset of these individuals has attenuated descending analgesic activity that is restored when they are administered a selective noradrenergic/serotonergic reuptake inhibitor (NSRI), milnacipran. We hypothesize that a subset of IC/PBS patients has attenuated noradrenergic and serotonergic activity in descending analgesic pain processing pathways, and that this will be identifiable both by experimental pain testing and fMRI, and that this will be reversed when these individuals are administered a specific norepinephrine-serotonin reuptake inhibitor, milnacipran. The specific aims of this study are to: 1) To demonstrate that some 1C patients have attenuated descending noxious inhibitory control (DNIC), as has been identified in FM, 2) To show that when 1C patients are given milnacipran, a norepinephrine-serotonin reuptake inhibitor, these individuals will have restoration of DNIC, 3) To demonstrate that the improvements of DNIC identified by experimental pain testing can also be shown using fMRI, 4) To show that the improvements in DNIC with the administration of milnacipran to IC/PBS patients are accompanied by improvements in clinical symptoms, and 5) To show that genetic polymorphisms involving catachol-O-methyl-transferace (COMT) and beta 2 and -3 adrenoreceptors. This study will not only probe a specific mechanism in 1C that has been shown to be dysfunctional in FM and IBS (the absence of appropriate descending analgesic activity), but also demonstrate "proof-of-concept" that this abnormality is due to a specific molecular mechanism. Although dual reuptake inhibitors, e.g., tricyclics and SNRI/ NSRIs are agreed to be efficacious in central pain states and this activity has been suspected to be due to augmented descending analgesic activity, this mechanism has never been definitively supported, thus these studies will be important in the broader pain field as well as advancing knowledge in 1C.